Presence of tophi is associated with a rapid decline in the renal function in patients with gout - Nature
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OPEN Presence of tophi is associated
with a rapid decline in the renal
function in patients with gout
Yoon‑Jeong Oh & Ki Won Moon*
We aimed to compare clinical characteristics of patients with and without tophi at the time of the
diagnosis of gout and investigate the association of tophi and renal function in gout patients. The
patients who were first diagnosed with gout at the Kangwon National University Hospital were
retrospectively studied. Patients were divided into 2 groups according to the presence of tophi at the
diagnosis. We compared clinical characteristics and the progression of renal dysfunction between the
two groups. Of 276 patients, 66 (25.5%) initially presented with tophi. Tophi group was older, had a
longer symptom duration, and a higher prevalence of multiple joint involvement than those without
tophi. In multivariate logistic regression analysis, prolonged symptom duration and multiple joint
involvement were significantly associated with increased risk of formation of tophi. The decline in the
eGFR was more prominent in patients with tophi than in those without (− 4.8 ± 14.5 vs. − 0.7 ± 11.9 ml/
min/1.73 m2/year, respectively; P = 0.039). The presence of tophi was significantly associated with a
rapid decline in the eGFR (β = − 0.136; P = 0.042). In conclusion, the presence of tophi was associated
with a rapid declining renal function. Therefore, an early diagnosis and closely monitoring of renal
function might be important in gout patients with tophi.
Uric acid primarily exists as soluble monosodium urate (MSU) under physiological conditions in humans. How-
ever, when the urate concentration exceeds the limit of solubility, it increases the risk of MSU crystal formation
and precipitation1. Hyperuricemia results in serious complications including gout, tophi, kidney stones, urate
nephropathy, and the subsequent loss of kidney f unction2. Of these, gout is the most common inflammatory
arthritis resulting from a chronic deposition of MSU crystals in the joints and other soft tissues3.
Tophi is primarily formed due to an inflammatory response to MSU crystals in which inflammatory cells
infiltrate the MSU crystals around the joints. This usually occur in longstanding, undiagnosed, or improperly con-
trolled cases of gout, though in rare cases, they may present as an early-stage symptom of gout4,5. Intra-articular
tophi may sometimes result in bone destruction, joint deformities, and dysfunction, and muscle weakness which
can adversely affect the patient’s quality of life6–8. Furthermore, a recent report showed that the presence of tophi
was also associated with an increased risk of mortality in gout p atients9.
It has been reported that several studies about mutual relationship between gout and its associated comor-
bidities. A previous study reported that patients with tophaceous gout show an increased risk of cardiovascular
diseases (CVD)10. It is well known that hyperuricemia is potentially associated with the development and pro-
gression of comorbidities, including CVD, metabolic syndrome, and renal disease11. Recently, the prevalence of
comorbidities among gout patients has been also increasing with the rapid rise in the number of gout p atients12.
In addition, several comorbidities including heart failure (HF), hypertension (HTN), and diabetes mellitus (DM)
may play a dominant role in MSU crystal deposition in these patients13.
Lu et al. reported that patient with early-onset tophaceous gout are more likely to develop renal dysfunction14,
however, few studies have investigated if the presence of tophi is related with the progression of renal dysfunction
in gout patients. Therefore. this study aimed to compare the clinical characteristics of patients with and without
tophi at the time of diagnosis of gout and investigate the association of tophi and renal function in gout patients.
Results
Baseline characteristics of gout patients with and without tophi. From a total of 257 patients
with gout, 66 (25.7%) had tophi whereas the remaining 191 (74.3%) had no tophi at the time of the initial visit.
The baseline characteristics of the study patients with and without tophi are shown in Table 1. The mean age
of patients in the tophi group at diagnosis was significantly higher than that of patients in the no tophi group
Division of Rheumatology, Department of Internal Medicine, Kangwon National University School of Medicine, 156,
Baengnyeong‑ro, Chuncheon‑si, Gangwon‑do, Republic of Korea. *email: kiwonmoon@kangwon.ac.kr
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Variables Tophi (N = 66) No tophi (N = 191) P value
Age at diagnosis (years) 61.0 ± 15.9 52.0 ± 17.2 < 0.001
Age at symptom onset (years) 54.8 ± 17.0 49.8 ± 17.3 0.051
Gender (male) 58 (87.9) 179 (93.7) 0.179
Symptom duration (months) 63.7 (11.0–147.0) 17.9 (2.6–56.3) < 0.001
Renal stone 6/58 (10.3) 18/150 (12.0) 0.814
Family history 3 (4.5) 11 (5.8) 1.0
Gout flares (≥ 3 per year) 6 (9.1) 9 (4.7) 0.223
Type of ULT 0.185
Febuxostat 37 (56.1) 125 (65.4)
Allopurinol 29 (43.9) 66 (34.6)
Colchicine use 53 (80.3) 151 (79.1) 1.0
Diuretics use 9 (13.6) 28 (14.7) 0.843
Aspirin use 10 (15.2) 37 (19.4) 0.580
Comorbidities
Hypertension 38 (57.6) 86 (45.0) 0.088
Diabetes mellitus 9 (13.6) 34 (17.8) 0.566
Cardiovascular disease 16 (24.2) 41 (21.5) 0.731
Heart failure 2 (3.0) 9 (4.7) 0.734
Dyslipidemia 20 (30.3) 65 (34.0) 0.650
Hypertriglyceridemia 25 (49.0) 74 (48.7) 1.0
2)
Chronic kidney disease (eGFR < 60 ml/min/1.73 m 17 (25.8) 46 (24.1) 0.868
Dementia 1 (1.5) 3 (1.6) 1.0
Past history of cancer 3 (4.5) 18 (9.4) 0.299
Charlson comorbidity index 2.9 ± 2.3 2.5 ± 2.8 0.292
Laboratory findings
Uric acid (mg/dL) 8.8 ± 2.2 9.0 ± 1.8 0.487
BUN (mg/dL) 21.0 ± 9.7 18.4 ± 10.1 0.067
Cr (mg/dL) 1.1 ± 0.4 1.2 ± 0.5 0.782
eGFR (ml/min/1.73m2) 76.2 ± 26.0 81.6 ± 28.5 0.164
Total cholesterol (mg/dL) 174.3 ± 42.0 180.9 ± 47.3 0.306
Triglyceride (mg/dL) 229.8 ± 177.3 244.6 ± 170.6 0.622
LDL-C (mg/dL) 103.4 ± 33.7 107.4 ± 38.7 0.504
HDL-C (mg/dL) 44.2 ± 14.1 44.2 ± 11.7 0.979
Table 1. Baseline characteristics according to the presence of tophi. Results are expressed as the mean ± SD,
as the median (interquartile range, IQR), or as number (%). ULT urate lowering therapy, BUN blood urea
nitrogen, Cr creatinine, eGFR estimated glomerular filtration rate, LDL-C low-density lipoprotein cholesterol,
HDL-C high-density lipoprotein cholesterol.
(61.0 ± 15.9 years vs. 52. 0 ± 17.2 years, respectively; P < 0.001). The gender distribution was similar between the
2 groups. The median duration of symptoms prior to the diagnosis of gout was significantly longer in the tophi
group than in the no tophi group (63.7 [11.0–147.0] months vs. 17.9 [2.6–56.3] months, respectively; P < 0.001).
The 2 groups did not differ with respect to factors such as a history of renal stones, the family history, number of
gout flares (≥ 3 per year), concomitant medication (colchicine, diuretics, and aspirin use), type of urate lowering
therapy (ULT), presence of comorbidities (HTN, DM, CVD, HF, dyslipidemia, hypertriglyceridemia, chronic
kidney disease [CKD], dementia, and past history of cancer). Among the study subjects, 162 (63.0%) patients
were initially treated with febuxostat and 95 (37.0%) patients were treated with allopurinol. In the febuxostat
group, 160/162 (98.8%) patients continued taking febuxostat during the follow-up period, and 2 patients dis-
continued the drug. In the allopurinol group, 84 patients changed to febuxostat and 11 patients stopped taking
allopurinol. At baseline, the uric acid, blood urea nitrogen (BUN), creatinine (Cr) and estimated glomerular
filtration rate (eGFR) values, too, did not differ between the 2 groups.
Characteristics of joint involvement in patients with and without tophi. Table 2 shows a compar-
ison of the characteristics of the affected joints in patients with and without tophi. The mean number of tophi in
patients of the tophi group was 2.3 ± 1.9. At baseline, the number of affected joints of patients in the tophi group
was much higher than that of patients in the no tophi group (3.0 ± 2.1 vs. 1.4 ± 0.6, respectively; P < 0.001). The
involvement of the upper extremities was much more prevalent in patients of the tophi group than in patients of
the no tophi group (36.4% vs. 7.3%, respectively; P < 0.001). In contrast, the involvement of the lower extremi-
ties was much less prevalent in the patients of the tophi group than in patients of the no tophi group (89.4% vs.
99.5%, respectively; P < 0.001). The involvement of both upper and lower extremities was much higher in the
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Variables Tophi (N = 66) No tophi (N = 191) P value
Mean tophi number 2.3 ± 1.9
Number of involved joints 3.0 ± 2.1 1.4 ± 0.6 < 0.001
Involvement of only large joints 12 (18.2) 46 (24.1) 0.394
Involvement of only small joints 28 (42.4) 114 (59.7) 0.021
Involvement of multiple joints 34 (51.5) 18 (9.4) < 0.001
Involvement of upper extremities 24 (36.4) 14 (7.3) < 0.001
Involvement of lower extremities 59 (89.4) 190 (99.5) < 0.001
Involvement of upper and lower extremities 15 (22.7) 13 (6.8) 0.001
Table 2. Involved joints in patients with gout at baseline. Results are expressed as the mean ± SD, or as number
(%).
Univariate Multivariatea
Baseline variable OR (95% CI) P OR (95% CI) P
Age at diagnosis (years) 1.033 (1.015–1.051) < 0.001
1.023 (0.997–1.050) 0.088
Gender (male) 2.057 (0.802–5.279) 0.133
Symptom duration (months) 1.014 (1.009–1.019) < 0.001 1.010 (1.004–1.017) 0.001
Number of involved joints 3.871 (2.574–5.821) < 0.001 3.027 (1.831–5.004) < 0.001
Involved of large joint 2.428 (1.366–4.316) 0.003
0.796 (0.350–1.809) 0.586
Involved of small joint 1.293 (0.648–2.582) 0.466
Involve of upper extremities 7.224 (3.447–15.142) < 0.001 2.095 (0.768–5.719) 0.149
HTN 1.657 (0.941–2.916) 0.080
CVD 1.171 (0.605–2.266) 0.640
1.077 (0.491–2.360) 0.854
CKD 1.094 (0.575–2.082) 0.785
Baseline uric acid (mg/dL) 0.940 (0.804–1.099) 0.437
Table 3. Logistic regression analysis for the presence of tophi in study subjects. OR odds ratio, CI confidence
interval, HTN hypertension, CVD cerebrovascular disease, CKD chronic kidney disease. a Adjusted for age at
diagnosis, symptom duration, number of involved joints, involved of large joint, involve of upper extremities,
and HTN.
patients of the tophi group than in patients of the no tophi group (22.7% vs. 6.8%, respectively; P = 0.001). Soli-
tary involvement of the small joints was more frequent in the patients of the no tophi group than in patients of
the tophi group (59.7% vs. 42.4%, respectively; P = 0.021).
Risk factors associated with the development of tophi at the time of diagnosis of gout. Mul-
tivariate logistic regression analysis was performed to evaluate the risk factors associated with the development
of tophi at the time of diagnosis of gout in the study patients (Table 3). After adjusting for the clinical variables, a
prolonged duration of symptoms (Odds ratio [OR], 1.010; 95% confidence interval [CI], 1.004–1.017; P = 0.001)
and a high number of involved joints (OR, 3.027; 95% CI, 1.831–5.004; P < 0.001) were found to be independent
risk factors for the presence of tophi at the initial diagnosis of gout in this study.
Follow‑up data in study subjects. The median duration of follow-up was significantly longer in the tophi
group than in the no tophi group (61.9 [22.6–91.6] months vs. 34.9 [18.7–66.4] months, P = 0.004) (Table 4). Out
of 257 patients, 244 patients maintained the ULT during the follow-up period, and 13 patients discontinued it.
Patients that received non-steroidal anti-inflammatory drugs (NSAIDs) were 43 (65.2%) in patients with tophi
and 127 (66.5%) in patients without tophi (P = 0.881). There was no significant difference in NSAIDs consump-
tion days between the two groups (34.9 ± 76.0 days/year vs. 24.7 ± 88.5 days/year, P = 0.404). Moreover, there was
no significant difference in the mean uric acid level during follow-up between the two groups (5.3 ± 1.4 in the
tophi group vs. 5.4 ± 1.2 in the no tophi group, P = 0.619). There was also no significant difference in the number
of patients who reached the treatment target of more than 80% between the two groups (34 [51.5%] in the tophi
group vs. 93 [48.7%] in the no tophi group, P = 0.775). The rate of decline in the eGFR was significantly higher
in the tophi group than in the no tophi group (− 4.8 ± 14.5 ml/min/1.73m2/year vs. − 0.7 ± 11.9 ml/min/1.73m2/
year, respectively; P = 0.039) (Fig. 1).
Evaluation of the presence of tophi as an independent risk factor for a rapid decline in the
eGFR in gout patients. The risk factors associated with a rapid decline in the eGFR were analyzed using
linear regression analysis (Table 5). After adjusting for symptom duration, eGFR at baseline, presence of tophi,
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Variables Tophi (N = 66) No tophi (N = 191) P value
Follow-up duration (months) 61.9 (22.6–91.6) 34.9 (18.7–66.4) 0.004
Mean uric acid (mg/dL) 5.3 ± 1.4 5.4 ± 1.2 0.619
Maintenance of ULT 64 (97.0) 180 (94.2) 0.525
Response of ULT 34 (51.5) 93 (48.7) 0.775
NSAID use 43 (65.2) 127 (66.5) 0.881
NSAID consumption (days/year) 34.9 ± 76.0 24.7 ± 88.5 0.404
eGFR decline rate (ml/min/1.73m2/year) − 4.8 ± 14.5 − 0.7 ± 11.9 0.039
Table 4. Changes in the uric acid, eGFR decline, and medications during the follow-up period. Results
are expressed as the mean ± SD, or as number (%). ULT urate lowering therapy, NSAID non-steroidal anti-
inflammatory drugs, eGFR estimated glomerular filtration rate.
Figure 1. Changes in eGFR in gout patients with or without tophi. Decline of the eGFR in the tophi group
was − 4.8 ± 14.5 ml/min/1.73m2/year, while that in the no tophi group was − 0.7 ± 11.9 ml/min/1.73m2/year
(P = 0.039).
Univariate Multivariatea
Baseline variable β P β P
Age at diagnosis (years) − 0.048 0.441
Gender (male) − 0.066 0.295
Symptom duration (months) − 0.122 0.05 − 0.045 0.504
Number of involved joints − 0.032 0.611
Use of NSAIDs − 0.017 0.780 0.044 0.490
Type of ULT − 0.070 0.260 − 0.079 0.198
Mean uric acid (mg/dL) 0.030 0.636 0.089 0.164
eGFR (ml/min/1.73m2/year) − 0.207 0.001 − 0.247 < 0.001
Presence of tophi − 0.143 0.022 − 0.136 0.042
Table 5. Linear regression analysis for eGFR decline in study patients. NSAID non-steroidal anti-
inflammatory drugs, ULT urate lowering therapy, eGFR estimated glomerular filtration rate. a Adjusted for
symptom duration, use of NSAID, type of ULT, mean uric acid levels, baseline eGFR and tophi.
use of NSAIDs, type of ULT, and mean uric acid levels, the eGFR at baseline (β = − 0.247; P < 0.001) and the pres-
ence of tophi at diagnosis (β = − 0.136; P = 0.042) were significantly associated with a rapid decline in the eGFR
in study subjects.
Discussion
This study demonstrated that a prolonged duration of symptoms and a high number of involved joints were sig-
nificantly associated with the presence of tophi at the time of diagnosis in gout patients. In addition, we showed
that the presence of tophi at diagnosis was significantly associated with a declining renal function.
A suboptimal treatment of gout contributes to increased frequency of gout attacks leading to chronic tophi
formation and joint deformities. It has been reported that the prevalence of tophi in patients with gout varies from
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3 to 21%15. During a gout attack, the MSU crystals activate monocytes and macrophages with the production of
chemotactic substances causing a massive infiltration of neutrophils in the joint fluid and synovial membrane.
Simultaneously, these crystals induce the secretion of a variety of cytokines, prostanoids, chemotactic factors,
and other proteins which amplify the inflammatory process through the recruitment of inflammatory cells, the
upregulation of adhesion molecules, and the stimulation of the acute phase r esponse16,17. Therefore, the stimu-
lation of immune and inflammatory cells by the MSU crystals may lead to acute pain if not properly resolved,
resulting in tophi formation and joint damage in the form of bone erosions and joint dysfunction. The objective
of long-term management of gout is to maintain low levels of serum uric acid and prevent chronic complications
such as tophi formation and chronic damage of the affected joints.
Interestingly, joint involvements of upper extremities were more observed in the tophi group compared to
no tophi group in this study. Gout attack occurs predominantly in the first metatarsophalangeal joint (1st MTP
joint), and many as 50–70% of first gout attacks occurs at this j oint18. Our study also showed that most patients
had symptoms in the 1st MTP joint of the lower extremities. However, since the duration of symptom was much
longer in the tophi group, several joints would be inevitably affected and the involvement of the upper extremities
was more frequently observed in the tophi group than in the no tophi group (36.4% vs. 7.3%, P < 0.001) (Table 2).
A previous study reported that the duration of the disease and number of involved joints were associated with
the development of tophi in gout patients19. The current study also demonstrated that a prolonged duration of
symptoms without treatment and a high number of affected joints were significantly associated with tophi for-
mation (Table 3). In terms of uncontrolled hyperuricemia, a long period of chronic gouty symptoms was closely
associated with the occurrence of tophaceous nodules in gout patients.
Previous studies have shown that multiple factors including an advanced age or a reduced creatinine clearance
at baseline are associated with the early formation of t ophi19,20. Gancheva et al. reported that a reduced creatinine
clearance was an independent risk factor for tophaceous gout21. Lu et al. also showed that pre-existing tophi
play an important role in decreasing the eGFR in early-onset juvenile tophaceous gout patients, whose mean
age of onset of gout was 15.7 years for tophi patients and 16.8 years for non-tophi p atients14. The current study,
in which the mean age of onset of gout was 51.1 years, also showed that the presence of tophi at diagnosis was
associated with a progressive decline in renal function even though there was no difference in the baseline renal
function between the groups with and those without tophi. Previous studies have reported that the prevalence of
gout has increased in recent decades, and there is a shift in the age of onset of gout to a much younger age group
than before because of an increased prevalence of metabolic syndrome, obesity, and from diet-related causes22.
Along with metabolic syndrome, the prevalence of CKD is also increasing in these populations together with an
increased prevalence of C VD23. In addition, increased MSU crystal deposition is associated with an increased
risk of urate renal stone formation. Therefore, tophi, as markers of long-standing gout, are associated with an
increased risk of progression of CKD. Several pathophysiological associations between the presence of tophi and
a decline in renal function can be explained. NSAIDs are nephrotoxicitic agents, and long-term use of NSAIDs
is associated with an increased risk of NSAIDs-related n ephrotoxicity24. It is a possible that a patient with tophi
might be frequently exposed to analgesics including NSAIDs because they suffer from inflammation and its
related symptoms. However, there was no difference in the number of NSAIDs consumption days between the
two groups in our study. There is another possibility that it is related to urate nephropathy. A previous study by
Ayoub et al., reported that biopsy-proven medullary tophi may contribute the progression of C KD25. Medullary
tophi may destroy and block the collecting system in the kidneys and induce CKD. This pathologic abnormality
might be prevalent in the tophaceous gout patients. However, most of the patients in this study did not undergo
renal image, so further studies are needed.
There are several limitations to this study. First, the present study has a retrospective cohort design and the
study population was constituted by patients registered at a single medical center. Therefore, the size of the study
sample was relatively small. Second, as this study was based on data derived from electronic medical records, it
lacks detailed further follow-up data, pre-existing tophi may have remained undetected by both the individual
as well as the healthcare professionals. Third, as the diagnosis of few of the tophi was not confirmed via micros-
copy, on ultrasound, or using dual energy computed tomography, they could not be distinguished from other
similar diseases characterized by crystal deposition including the deposition of calcium pyrophosphate crystals.
Finally, since the duration of symptoms was longer in the tophi group, we are not able to exclude long-standing,
untreated patients with gout in this group. Subgroup analysis was performed according to symptom duration of
gout. Out of 101 patients with symptom durations of < 1 year, 18 (17.8%) patients had tophi. Meanwhile, 48/156
(30.8%) patients with symptom durations of ≥ 1 year were in the tophi group. In the subgroup with a duration
of symptoms of < 1 year, the rate of decline in eGFR was − 2.9 ± 5.7 ml/min/1.73m2 /year in patients with tophi
and 0.1 ± 15.4 ml/min/1.73m2/year in patients without tophi (P = 0.421). In patients with symptom duration
of ≥ 1 year, the decline in eGFR was − 5.6 ± 16.6 ml/min/1.73 m2/year in the tophi group and − 1.3 ± 8.3 ml/
min/1.73m2/year in the no tophi group (P = 0.097). Regardless of the duration of symptom, we found that the
eGFR of patients with tophi tended to decrease more rapidly than those without tophi, but this was not statisti-
cally significant even though it might be because the number of subgroup subjects was relatively small. Therefore,
further large-scaled study is needed to confirm our results. However, the strength of the present study is that 2
groups were relatively well balanced without significant differences in the renal function, uric acid levels, and
use of diuretics at the time of diagnosis of gout. This made it easier to identify the risk factors responsible for the
progression of renal dysfunction in gout patients.
In conclusion, our results suggest that a prolonged duration of symptom prior to the diagnosis of gout and a
high number of involved joint may contribute to the presence of tophi as the initial manifestation at diagnosis.
In addition, the presence of tophi at the time of diagnosis of gout was significantly associated with a rapid decline
in the renal function. Therefore, early diagnosis and appropriate treatment are essential to prevent a further
deterioration of the kidney function in tophaceous gout patients.
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Methods
A total of 257 patients who were first diagnosed with gout at the Kangwon National University Hospital (KNUH)
from January 2012 to December 2018 were included in this study. All study subjects were prescribed febuxostat
or allopurinol as ULT and maintained it for more than 3 months. The following patients were excluded: age at the
time of gout diagnosis < 18 years, patients who were treated with ULT for asymptomatic hyperuricemia, patients
on dialysis, and those with a follow-up period of less than 3 months. Gout was diagnosed according to the 2015
American College of Rheumatology/European League Against Rheumatism Gout Classification C riteria26. The
frequency of the gout flares and the date of the initial symptoms were self-reported by the patients. The dura-
tion of symptoms was defined as the duration between the first clinical manifestation of gout and the initiation
of ULT. The presence and number of tophi were determined by experienced rheumatologists during the initial
assessment. Most patients with gout that have tophi were found to have monosodium urate crystal using polar-
ized light microscopy by arthrocentesis, and some of those were diagnosed using imaging modalities, such as
ultrasonography or dual energy computerized tomography, and others were clinically confirmed by physical
examination without joint fluid analysis. Tophi were classified according to the size (small or large) and location
of the affected joints (upper extremities [elbow, wrist, metacarpophalangeal joints, proximal phalangeal joints,
and distal phalangeal joints] or lower extremities [knee, ankle, and metatarsophalangeal joints]). The study was
approved by the Institutional Review Board of Kangwon National University Hospital and conducted in accord-
ance with the Declaration of Helsinki (KNUH IRB protocol number: 2019-12-009). Informed consent was waived
by the KNUH institutional review board due to the retrospective nature of this study.
Data collection. All data were retrieved from the electronic medical records of KNUH. Demographic data,
including the age, gender, family history, history of renal stones, frequency of gout flares, involved joints, con-
comitant medications (ULT, NSAIDs, colchicine, aspirin, diuretics including furosemide and thiazide), and data
on comorbidities such as HTN, DM, CVD, HF, dyslipidemia, hypertriglyceridemia, CKD, dementia, and a past
history of cancer were gathered. We also collected the following biochemical laboratory data: serum uric acid,
BUN, Cr, eGFR, total cholesterol, triglyceride, low-density lipoprotein cholesterol and high-density lipoprotein
cholesterol levels at the time of diagnosis. The uric acid levels at each outpatient visit were obtained. In addi-
tion, the levels of BUN, Cr, and eGFR at the last follow-up were also obtained. To find out the response to ULT,
whether the uric acid level reached the ≤ 6.0 mg/dL was assessed at each outpatient visit. We defined a patient as
the response group when their uric acid levels reached ≤ 6.0 mg/dL at 80% or more of total number of visits. The
change in the eGFR level from that at the time of diagnosis of gout to that at the last follow-up date was calcu-
lated. The eGFR was determined using the Modified of Diet in Renal Disease f ormula27.
Statistical analysis. Continuous variable are expressed as the mean ± standard deviation (SD) or as the
median (interquartile range, IQR), while categorical variables are expressed as number percentages (%). The
Chi-square test was used to compare the categorical variables between patients with and without tophi. Con-
tinuous variables were compared using Student’s t-test for parametric data or the Mann–Whitney U test for
nonparametric data. Multivariate logistic regression analysis was performed to estimate the relative risk of tophi
formation in the study subjects. Variables that had a P value of < 0.1 on univariate analysis were selected for
multivariate analysis. In addition, factors associated with a decline in the eGFR were identified using the linear
regression model. The clinical variables that had a P value of < 0.1 on univariate analysis, use of NSAIDs, type of
ULT, and mean uric acid levels were used for multivariate analysis. All statistical analyses were performed using
SPSS (version 23.0, Chicago, IL). A P value < 0.05 was considered statistically significant.
Received: 18 November 2020; Accepted: 18 February 2021
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Author contributions
Y.J.O. conducted the analyses and led the writing of the manuscript. K.W.M. supervised the manuscript.
Competing interests
The authors declare no competing interests.
Additional information
Correspondence and requests for materials should be addressed to K.W.M.
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